Penicillins and cephalosporins are β-lactam antibiotics that are widely and frequently used in the clinic. However, the acquisition of resistance to β-lactam antibiotics by various pathogens has had a damaging effect on maintaining the effective treatment of bacterial infections. The most significant known mechanism related to the acquisition of bacterial resistance is the production of class A, C, and D β-lactamases having a serine residue at the active center. These enzymes decompose the β-lactam antibiotic, resulting in the loss of the antimicrobial activities. Class A β-lactamases preferentially hydrolyze penicillins while class C β-lactamases have a substrate profile favoring cephalosporins.
Commercially available β-lactamase inhibitors, e.g., clavulanic acid, sulbactam, and tazobactam, are known and these inhibitors are effective mainly against class A β-lactamase producing bacteria, and used as a mixture with a penicillin antibiotic. However, 250 types or more of β-lactamases have been reported to date, including resistant bacteria which produce class A KPC-2 β-lactamase decomposing even carbapenem.
In recent years, infectious diseases caused by the above-mentioned resistant bacteria as pathogenic bacteria are found not only in severe infectious disease but also occasionally in community-acquired infectious disease. The currently available β-lactamase inhibitors are insufficient to inhibit the incessantly increasing β-lactamase and novel β-lactamase inhibitors that are required for the difficult treatment of bacterial infectious diseases caused by resistant bacteria. The development of antibacterial agents as well as β-lactamase inhibitors is in strong demand as the commercially available inhibitors become increasingly ineffective.
One of these antibacterial agents, (2S, 5R)—N-(2-aminoethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide, represented by Compound (I), is a “potent, broad-spectrum, non-β-lactam β-lactamase inhibitor” useful for antibiotic-resistant Gram-negative bacteria (Li, H.; Estabrook, M.; Jacoby, G. A.; Nichols, W. W.; Testa, R. T.; Bush, K. Antimicrob Agents Chemother 2015, 59, 1789-1793.) There are four crystalline forms of (2S, 5R)—N-(2-aminoethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide previously characterized and known in the art (see, e.g., International Publication no. WO 2015/053297).
While other crystalline forms have been previously characterized, large scale-up manufacturing processes which afford good reproducibility, high stability and high yield have not been achieved. When developing technologies for a commercial process, there are several factors and properties to consider when converting a small-scale lab process to a large manufacturing process suitable for clinical use.
A particular pharmaceutical composition may be preferable in certain circumstances in which certain aspects, such as ease of preparation, stability, etc., are deemed to be critical. In other situations, a different pharmaceutical composition may be preferred for greater solubility and/or superior pharmacokinetics.